HOPKINS SCIENTISTS FIND ANOTHER GENE LINKED TO PANCREATIC CANCER

Johns Hopkins scientists have identified a gene involved in half of all cases of pancreatic cancer, the nation's fifth leading cancer killer. The discovery gives insight into the nature of the cancer and eventually may lead to practical ways to diagnose tumors early and reverse the defective gene's damage.

The gene, called DPC4, joins a few other tumor suppressor genes, including p53 and p16, that have been identified as having pivotal roles in many cancers, according to the Hopkins researchers. The discovery, published in the Jan. 19 issue of Science, is a crucial step in understanding the genetic basis of pancreatic cancer, says Scott Kern, M.D., the study's senior author and an assistant professor of oncology and pathology. Pancreatic cancer kills more than 25,000 people annually in the United States.

"The old saying -- To beat your enemy, you must know your enemy' -- is as true for science as it is for war," says Kern. "Now we know our enemy much better."

Previous studies at Hopkins and elsewhere have shown that 90 percent of pancreatic cancers have a genetic abnormality on chromosome 18q -- either a deletion (most or all of a gene is missing) or a mutation (a change in DNA bases that make up a gene). The Hopkins research team studied 84 tumor samples. They found that 52 percent had genetic deletions or mutations in one stretch of the chromosome, which always disrupted a newly described
gene, called DPC4. The study's results suggest that DPC4 is a tumor suppressor gene involved in the cells' pathways for sending signals. The deletions and mutations may thus block a key protein from doing its job of regulating the cell's growth. A tumor suppressor gene normally helps prevent cancer from developing, but when a defect inactivates the gene, cells may multiply uncontrollably.

The Hopkins research team found DPC4 by looking for a genetic abnormality called homozygous deletions (a loss of both alleles, or pairs of the same gene). The double loss inactivates the tumor suppressor gene -- like losing the brakes on a car -- and leads to the runaway cell growth that results in cancer. The scientists found that 30 percent of the tumor samples had homozygous deletions at the DPC4 site and 22 percent of those without homozygous deletions had mutations that could inactivate the gene.

Four major genes are known to be involved in pancreatic cancer. The Hopkins team plans to continue using the homozygous deletions method to search for more cancer genes. This method allows investigators to narrow the sites of abnormalities not because something is out of place but because something that should be there is missing.

"It's like determining that a lake may be polluted not because of trash along the shore but because the fish are missing," says Kern. "The bigger picture of our studies is that homozygous deletions may help us discover other genes involved in other cancers more quickly." Indeed, he added, the recent identification of a familial breast cancer gene used information from a Hopkins pancreatic cancer deletion.

Scientists developing antitumor drugs consider an inactivated tumor suppressor gene to be the main "target." But another possibility is using "bystander" genes, or the dozens of nearby genes that also are inactivated when a homozygous deletion occurs. While the target gene may not be able to be reactivated, the lost bystander genes result in lowered levels of enzymes that could serve as the "biochemical hook to select the cancer cells and kill them," says Kern. Therefore, by identifying homozygous deletions, researchers hope to devise entirely new therapeutic strategies.

A DPC4-like gene also is present in a commonly studied fruit fly and worm; in both the insects and humans, inactivating the gene causes lethal abnormalities.